The proposed training in developmental biology and oncology will provide Prof. Beebe with a foundation of biological knowledge and skills (immediate goal) allowing him to develop a comprehensive multidisciplinary cancer research program that fully leverages the cellular/technology interface to explore basic questions pertinent to understanding the biology of tumor development (long term goal). The career development plan integrates didactic training, laboratory skills, and hands-on research under the guidance of Prof. Caroline Alexander of the McArdle Laboratory for Cancer Research. The research is aimed at understanding the regulation of the progenitor fraction in the mammary gland. Recently a description of mammary cells with progenitor characteristics (including BrDu retention, expression of ABC transporter, and morphology/position) has emerged. Unlike the majority of mammary epithelial cells, these long-lived progenitors can be propagated in suspension (mammospheres) and differentiate into both mammary lineages with the provision of appropriate stiumuli. Dr. Alexander's lab has found that in response to the Wnt oncogenic pathway, the progenitor fraction in mouse mammary gland is dysregulated, and this is accompanied by the development of preneoplastic hyperplasia in vivo. In the proposed research, Dr. Beebe will use the information derived from the study of neural and hematopoietic progenitor cells, to test whether the progenitor fraction in the mammary gland is normally actively regulated by factors secreted by cells at other stages of maturation. This hypothesis is not easy to address using traditional culture models. In order to test for growth-regulating cell interactions, progenitor cells (from mammospheres) will be mixed with differentiated cells. Micro scale engineering facilitates studies examining the importance of soluble effectors (no cell contact) as well as cell-associated effectors (cells in contact). The results of such studies will show whether the progenitor compartment is subject to growth regulation by other cell types in the mammary epithelium leading to a more complete understanding of the mechanisms of cancer development in the mammary gland. It is also possible that an improved understanding combined with new culture constructs will lead to a culture model that can support mannary ductal morphagenesis. Such a model would have a significant impact on breast cancer research.